Oral Presentation 10th Australian Peptide Conference 2013

NextGen Venomics: Natural, virtual and synthetic venoms for peptide drug discovery, target deorphanization and lead optimization (#65)

Reto Stöcklin 1
  1. Atheris Laboratories, Geneva, Switzerland

The animal kingdom includes 200’000 venomous species that developed over several hundred million years of evolution. Each venom typically consist of a unique cocktail of hundreds different molecules, mostly highly potent and selective bioactive ingredients falling within the class of well-structured medium-sized peptides. These biomolecules naturally possess a number of key drugability requirements: while poorly immunogenic, they are highly potent, selective, stable and soluble. In addition, they are a proven source for screening pharmaceutical targets that are difficult to address using standard medicinal chemistry approaches such as ion channels, transmembrane or circulating proteins. Dozens of venom-derived mini-protein drug candidates have been taken into drug development and six of these made it to clinical use1,2.

Usually, the first step in the search for new compounds is a bioassay, which is followed by a deconvolution process leading to isolation and characterization of the bioactive substance. While these conventional bioactivity-guided strategies have a proven track record, they are time and sample consuming . Today, the “Venomics” strategy that we pioneered3  combines state-of-the-art peptide synthesis, proteomics4 , transcriptomics5  and post-genomics technologies with specialized bioinformatics tools6 . This generates an abundance of valuable data in a very short period of time and using much smaller amounts of natural products.

We will present an innovative NextGen Venomics platform that is aimed at providing access to yet impossible to explore samples in an unprecedented manner through a combination of natural, synthetic and virtual venoms:

·    Pre-fractionation of venoms to produce libraries of natural venoms for HTS

·    Massive venom gland NextGen mRNA sequencing

·    Bioinformatics to extract sequences and produce the first virtual venoms

·    Original software to streamline the transcriptomics-assisted deconvolution process

·    An integrated in silico platform to screen virtual venoms and design optimized leads

·    Large-scale multiplex synthesis of peptides as first synthetic venoms libraries

  1. Harvey, A.L. and Stöcklin, R. (2012). From venoms to drugs: introduction. Editorial. Toxicon, 59(4):433-433
  2. Stöcklin, R. and Vorherr, T. (2011). Future perspectives of venoms for drug discovery. Pharmanufacturing: The international peptide review. (Nov. 2011):21-24
  3. Ménez, A., Stöcklin, R. and Mebs, D. (2006). 'Venomics' or: The venomous systems genome project. Editorial. Toxicon 47(3):255-259
  4. Violette, A., Biass, D., Dutertre, S., Koua, D., Piquemal, D., Pierrat, F., Stöcklin, R. and Favreau, P. (2012). Large-scale discovery of conopeptides and conoproteins in the injectable venom of a fish-hunting cone snail using a combined proteomic and transcriptomic approach. J. Proteomics. 75(17):5215-5225
  5. Terrat, Y., Biass, D., Dutertre, S., Favreau, P., Remm, M., Stöcklin, R., Piquemal, D. and Ducancel, F. (2011). High resolution picture of a venom gland transcriptome: case study with the marine snail Conus consors. Toxicon. 59(1):34-46
  6. Koua, D., Brauer, A., Laht, S, Kaplinski, L., Favreau, P., Remm, M., Lisacek, F. and Stöcklin, R. (2012). ConoDictor: a tool for prediction of conopeptide superfamilies. Nucleic Acids Res. 40(Web Server issue):W238-41